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Alternative survival pathways are commonly seen to be upregulated upon inhibition of receptor tyrosine kinases (RTK), including Her-2. It is established that treatment with Herceptin leads to selective overexpression and activation of epidermal growth factor receptor (EGFR) and Src which further contributes to oncogenesis in Herceptin resistant and triple negative breast cancer (TNBC) patients. Here, we show a co-regulated upregulation in the expression of Annexin A2 (AnxA2), a known substrate of Src and one of the regulators of EGFR receptor endocytosis, in Herceptin resistant and Her-2 negative breast cancer. Immunohistochemical expression analysis revealed a reciprocal regulation between Her-2 and AnxA2 in breast cancer clinical samples as well as in cell lines as confirmed by protein and RNA analysis. The siRNA and Herceptin mediated downregulation/inhibition of Her-2 in Her-2 amplified cells induced AnxA2 expression and membrane translocation. In this study we report a possible involvement of AnxA2 in maintaining constitutively activated EGFR downstream signaling intermediates and hence in cell proliferation, migration and viability. This effect was consistent in Herceptin resistant JIMT-1 cells as well as in Her-2 negative breast cancer. The siRNA mediated AnxA2 downregulation leads to increased apoptosis, decreased cell viability and migration. Our studies further indicate the role of AnxA2 in EGFR-Src membrane bound signaling complex and ligand induced activation of downstream signaling pathways. Targeting this AnxA2 dependent positive regulation of EGFR signaling cascade may be of therapeutic value in Her-2 negative breast cancer.
Pubmed ID: 22957061
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Cell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MCF-7 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC38 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line JIMT-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MCF-10A is a Spontaneously immortalized cell line with a species of origin Homo sapiens
View all literature mentionsCell line BT-474 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC1937 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC70 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SK-BR-3 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line BT-549 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC1143 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MDA-MB-231 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line JIMT-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentions